On adaptive control and particle filtering in the automatic administration of medicinal drugs

Automatic feedback methodologies for the administration of medicinal drugs offer undisputed potential benefits in terms of cost reduction and improved clinical outcomes. However, despite several decades of research, the ultimate safety of many--it would be fair to say most--closed-loop drug delivery approaches remains under question and manual methods based on clinicians' expertise are still dominant in clinical practice. Key challenges to the design of control systems for these applications include uncertainty in pharmacological models, as well as intra- and interpatient variability in the response to drug administration. Pharmacological systems may feature nonlinearities, time delays, time-varying parameters and non-Gaussian stochastic processes. This dissertation investigates a novel multi-controller adaptive control strategy capable of delivering safe control for closed-loop drug delivery applications without impairing clinicians' ability to make an expert assessment of a clinical situation. Our new feedback control approach, which we have named Robust Adaptive Control with Particle Filtering (RAC-PF), estimates a patient's individual response characteristic in real-time through particle filtering and uses the Bayesian inference result to select the most suitable controller for closed-loop operation from a bank of candidate controllers designed using the robust methodology of mu-synthesis. The work is presented as four distinct pieces of research. We first apply the existing approach of Robust Multiple-Model Adaptive Control (RMMAC), which features robust controllers and Kalman filter estimators, to the case-study of administration of the vasodepressor drug sodium nitroprusside and examine benefits and drawbacks. We then consider particle filtering as an alternative to Kalman filter-based methods for the real-time estimation of pharmacological dose-response, and apply this to the nonlinear pharmacokinetic-pharmacodynamic model of the anaesthetic drug propofol. We ultimately combine particle filters and robust controllers to create RAC-PF, and test our novel approach first in a proof-of-concept design and finally in the case of sodium nitroprusside. The results presented in the dissertation are based on computational studies, including extensive Monte-Carlo simulation campaigns. Our findings of improved parameter estimates from noisy observations support the use of particle filtering as a viable tool for real-time Bayesian inference in pharmacological system identification. The potential of the RAC-PF approach as an extension of RMMAC for closed-loop control of a broader class of systems is also clearly highlighted, with the proposed new approach delivering safe control of acute hypertension through sodium nitroprusside infusion when applied to a very general population response model. All approaches presented are generalisable and may be readily adapted to other drug delivery instances

Light-Enabled Identification of the Neuronal Substrates of Alkylphenol Anesthetics

General anesthetics are a critical class of drugs in modern medicine; however, the precise mechanisms by which they cause unconsciousness and unwanted side effects are largely undefined. In order to understand pharmacologic mechanisms of anesthetic action, drug interactions with macromolecular substrates and the subsequent functional consequences must be characterized. Analogs of general anesthetics that function as photolabels have been developed to assist in the identification of molecular targets. One such photolabel, meta-azi-propofol (AziPm), is an analog of the clinically used alkylphenol anesthetic propofol. In this work, AziPm is employed in a variety of experiments that aim to identify molecular substrates of propofol. Two proteins identified as propofol targets are more thoroughly examined: (1) the sirtuin deacetylase SIRT2 and (2) the mitochondrial voltage-dependent anion channel (VDAC). The binding sites of propofol on these proteins, and the in vitro functional consequences of propofol binding, are determined. Also described are the molecular interactions of VDAC with a separate ligand, cholesterol, which shares a binding site with propofol. In addition to molecular studies, a novel in vivo photolabeling technique, called optoanesthesia, that utilizes AziPm is introduced, and the behavioral phenotype induced by optoanesthesia in Xenopus laevis tadpoles is characterized. Finally, optoanesthesia is demonstrated with other ligands, including a photoactive analog of an anthracene anesthetic, and mechanistic insight into the pharmacology of this anthracene is revealed

A FRAMEWORK FOR CREDIBILITY ASSESSMENT OF SUBJECT-SPECIFIC PHYSIOLOGICAL MODELS

Physiological closed-loop controllers and decision support systems are medical devices that enable some degree of automation to meet the needs of patients in resource-limited environments such as critical care and surgical units. Traditional methods of safety and effectiveness evidence generation such as pre-clinical animal and human clinical studies are cost prohibitive and may not fully capture different performance attributes of such complex safety-criticalsystems primarily due to subject variability. In silico studies using subject-specific physiological models (SSPMs) may provide a versatile platform to generate pre-clinical and clinical safety evidence for medical devices and help reduce the size and scope of animal studies and/or clinical trials. To achieve such a goal, the credibility of the SSPMs must be established for the purpose it is intended to serve. While in the past decades significant research has been dedicated towards development oftools and methods for development and evaluation of SSPMs, adoption of such models remains limited, partly due to lack of trust in SSPMs for safety-critical applications. This may be due to a lack of a cohesive and disciplined credibility assessment framework for SSPMs. In this dissertation a novel framework is proposed for credibility assessment of SSPMs. The framework combines various credibility activities in a unified manner to avoid or reduce resource intensive steps, effectively identify model or data limitations, provide direction as to how to address potential model weaknesses, and provide much needed transparency in the model evaluation process to the decision-makers. To identify various credibility activities, the framework is informed by an extensive literature review of more mature modeling spaces focusing on non- SSPMs as well as a literature review identifying gaps in the published work related to SSPMs. The utility of the proposed framework is successfully demonstrated by its application towards credibility assessment of a CO2 ventilatory gas exchange model intended to predict physiological parameters, and a blood volume kinetic model intended to predict changes in blood volume inresponse to fluid resuscitation and hemorrhage. The proposed framework facilitates development of more reliable SSPMs and will result in increased adoption of such models to be used for evaluation of safety-critical medical devices such as Clinical Decision Support (CDS) and Physiological Closed-Loop Controlled (PCLC) systems

Endoscopy

Endoscopy is a fast moving field, and new techniques are continuously emerging. In recent decades, endoscopy has evolved and branched out from a diagnostic modality to enhanced video and computer assisting imaging with impressive interventional capabilities. The modern endoscopy has seen advances not only in types of endoscopes available, but also in types of interventions amenable to the endoscopic approach. To date, there are a lot more developments that are being trialed. Modern endoscopic equipment provides physicians with the benefit of many technical advances. Endoscopy is an effective and safe procedure even in special populations including pediatric patients and renal transplant patients. It serves as the tool for diagnosis and therapeutic interventions of many organs including gastrointestinal tract, head and neck, urinary tract and others

Accidental awareness during general anaesthesia in obstetric surgery

Accidental awareness during general anaesthesia (AAGA) occurs when a patient becomes unintentionally conscious during general anaesthesia, which may involve unpleasant memories of experiences during surgery. Contributory factors that may increase risk of AAGA coincide in pregnant women undergoing general anaesthesia for childbirth related surgery. Whilst obstetric general anaesthesia has largely been substituted by spinal and epidural (termed neuraxial) anaesthetic techniques, in which a mother can be awake and pain free during childbirth, general anaesthesia is still necessary to facilitate surgery rapidly in emergency situations or for mothers with certain medical conditions. In this thesis I investigate the distinct characteristics of general anaesthesia for pregnant women undergoing surgery for childbirth, whether these characteristics increase risk of AAGA, and changes to obstetric anaesthetic technique occurring in the context of wider anaesthetic developments over time. I provide evidence on the incidence, experiences, risk factors and psychological consequences of AAGA in peripartum women. Challenges to large scale clinical study of AAGA are explored and addressed in the design of a multi-centre, prospective, cross-sectional cohort study of women receiving general anaesthesia for obstetric surgery in 72 hospitals in England. A four-stage process for screening patients using direct questioning, verifying with corroborative detail, adjudicating and classifying descriptions of experiences is described. The interactional nature of research interviews, statistical modelling, psychological factors and the neurophysiology of memory are considered during development of study methodology. Psychological morbidity was assessed for 12 months after surgery. As part of an embedded study, descriptive epidemiology of obstetric patients and general anaesthesia techniques were identified, alongside risk factors for airway complications. A total of 3,115 patients were recruited, 12 of whom had certain/probable or possible AAGA: a prevalence of 0.39% or 1 in 256 (95%CI 149–500) for all obstetric surgery. Distressing experiences were reported by seven (0.22%) patients, paralysis by five (0.16%) and paralysis with pain by two (0.06%). Associations were identified between AAGA and patient risk factors (abnormal body mass index), organisational factors (out-of-hours surgery) and pharmacological factors (use of thiopental during induction of anaesthesia). Contextual factors relating anaesthesia for obstetric patients with AAGA and other anaesthesia complications, including difficult airway management, were evaluated. My study methodology and it’s context, in English public sector hospitals, identified a higher risk of AAGA in obstetric patients than previously detected using other methods and locations. These results have implications for healthcare policy of obstetric anaesthesia, informed consent of patients receiving general anaesthesia and post-natal screening care. I conclude on recommendations to minimise awareness risk for future patients and address the challenge of implementing systemic improvements in obstetric general anaesthesia care and patient safety

Alternative site for the placement of totally implantable vascular access device (TIVAD). A case report of two successful TIVAD implantations in the thigh after femoral vein catheterization

Background: Totally implantable venous access devices (TIVADs) have improved the quality of life for seriously ill and cancer patients. These devices represent a convenient option when long-term venous access is indicated. The Subclavian and Internal Jugular Veins are the vessels of choice for catheterization [1]. However, if it is not possible to catheterize them, an alternative vein should be sought for [2]. Femoral vein can be used in such cases [3].Clinical problem: In 2 cases, it was not possible to catheterise any vein ending in the Superior Vena Cava and implant a TIVAD in the chest wall, although this was very necessary for them. Femoral vein was chosen despite higher risk of complications.Case 1: A 47 years old female with a metastatic breast cancer and infected ulcerations of the anterior chest wall. Veins in both arms were occluded. Her implanted TIVAD could not be used. Case 2: A 44 years old female who had a newly diagnosed lung cancer and Superior Vena Cava Syndrome. She was treated by a high-dose anti-coagulants.Surgical intervention: The catheter was inserted in the left femoral vein using ultrasound-guided percutaneous technique. After making a small incision, PORT-A-CATH® II POWER P.A.C. single-lumen standard port was implanted subcutaneously in the anterior surface of the left thigh. Verification of the catheter’s tip intra-operatively was difficult in Case 1 due to fluoroscopy problems. Prior consideration of the required instruments prevented the occurrence of a similar problem in Case 2. We performed these operations in the University Hospital of Norrland in Sweden in 2013.Follow-up: Apart from later adjustment of the catheter positioning in Case 1, we did not get any complications or problems with the use of the TIVAD. Frequent flushing of the device was recommended. Patients’ and staff’s satisfaction were good. Conclusion: Placement of TIVAD in the thigh is to be considered when the veins of the neck and upper arm are not accessible or the area on the chest wall is not appropriate for implanting the device. Experience improves with more cases.References: 1- Di Carlo I, Toro A. Choice of venous sites. Surgical Implant/technique. Springer-Verlag, Italia, 2011;43-54. 2- Toro A, Mannino M, Cappello G et al. Totally implanted venous access devices implanted in saphenous vein. Relation between the reservoir site and comfort/discomfort of the patient. Ann Vasc Surg 2012;26(8):1127.e9-1127.e13. 3- Chen SY, Lin CH, Chang HM, Hsu HM, Yu JC. A safe and effective method to implant a totally implantable access port in patients with synchronous bilateral mastectomies: modified femoral vein approach. J Surg Oncol 2008;98(3):197-199

Readings in Advanced Pharmacokinetics

This book, “Readings in Advanced Pharmacokinetics - Theory, Methods and Applications”, covers up to date information and practical topics related to the study of drug pharmacokinetics in humans and in animals. The book is designed to offer scientists, clinicians and researchers a choice to logically build their knowledge in pharmacokinetics from basic concepts to advanced applications. This book is organized into two sections. The first section discusses advanced theories that include a wide range of topics; from bioequivalence studies, pharmacogenomics in relation to pharmacokinetics, computer based simulation concepts to drug interactions of herbal medicines and veterinary pharmacokinetics. The second section advances theory to practice offering several examples of methods and applications in advanced pharmacokinetics